ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity

Abstract

Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases. Here we used ASK1-deficient mice to show that ASK1 was selectively required for lipopolysaccharide-induced activation of p38 but not of Jnk or the transcription factor NF-kappaB. ASK1 was required for the induction of proinflammatory cytokines dependent on Toll-like receptor 4 (TLR4) but not TLR2 or other TLRs. Consistent with this, ASK1-deficient mice were resistant to lipopolysaccharide-induced septic shock. Lipopolysaccharide induced the production of intracellular reactive oxygen species, which was required for the formation of a complex of the adaptor molecule TRAF6 and ASK1 and subsequent activation of the ASK1-p38 pathway. Our data demonstrate that the reactive oxygen species-dependent TRAF6-ASK1-p38 axis is crucial for TLR4-mediated mammalian innate immunity.

Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways

“…These data therefore provide convincing evidence that the stimulation of TNF-␣ production by epithelial collecting duct cells activated by UPECs may directly activate the TLR4-independent production of MIP-2. Matsuzawa et al (65) have demonstrated that ASK1 specifically mediates LPS-induced TLR4 signaling via a ROSdependent activation of the TRAF6-ASK1-p38 pathway. This means that we cannot rule out the possibility that ROS produced locally by polymorphonuclear neutrophils or collecting duct cells may activate the TLR4-dependent TRAF6-ASK1-p38 pathway in Lps n MCDs and, together with TNF-␣, activate the TLR4-independent, ASK1-JNK-activated pathway that we have identified in Lps d MCDs.…”

Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages

“…Tpl2 activates ERK1/2 in TLR4 signllaing 4 . ASK1 is crucial for activation of p38 pathway in the signalling of TLR4, but not other TLRs 5 . MEKK1 is critical for JNK activation but inhibits ERK1/2 activation in LPS-and double-stranded RNA-induced TLR signalling 6 .…”

Redox Control of Apoptosis: An Update

“…Current results suggest a crucial role for ASK1 also in the activation of interferon (IFN) regulatory factor 3 (IRF3) (13) and the innate immune response to bacterial lipopolysaccharides (LPS) mediated by Toll-like receptor 4 (TLR4). In particular, Ichijo et al (38) found that ASK1 is required for LPS-induced sustained activation of p38 MAPK , but not c-Jun N-terminal kinase (JNK) or NF-B, by means of the formation of a complex with the adaptor molecule TNF receptor-associated factor 6 (TRAF6). In the pathway drawn, the role of the ASK1 inhibitory partner, thioredoxin (Trx), seems to be crucial as, by means of redoxsensitive vicinal thiols, it is oxidized to an intramolecular disulfide bridge-containing protein, changed in its structure and dissociated from ASK1, thus leading the phospho-signal to be propagated (29).…”